Fear of intracranial hemorrhage (ICH) is the primary reason that the only proven therapy for acute ischemic stroke is not provided to otherwise eligible patients. ICH also deters the development of more effective stroke therapies. New reperfusion strategies, using an intra-arterial (IA) approach, which may restore blood flow more effectively by providing therapy directly at the site of an occluded artery, are accompanied by higher rates of the mildest forms of ICH than proven intravenous thrombolytic therapy. While ICHs of all types have been considered adverse events in every acute stroke trial to date, the mechanistic significance and clinical impact of mild ICH subtypes is not known. The primary hypothesis is that acute ischemic stroke patients treated with IA therapies who have the mildest radiological subtype of ICH will be more likely to have early reperfusion and good clinical outcome than those without any ICH. Using the largest available trials with revascularization status, the PI will pursue the following specific aims: 1) determine the relationship between radiological subtypes of ICH and timing of successful revascularization and 2) determine the relationship of ICH subtypes to clinical outcome. The proposed work would: 1) guide the clinician's perceptions of the interplay between risk and benefit in the setting of reperfusion, 2) impact the interpretation of future Phase I and II reperfusion trial safety data, and 3) inform the design of future reperfusion strategies using hemorrhage prediction and hemorrhage prevention strategies. This research project will position the PI to independently design and implement an acute stroke trial with the goal of minimizing clinically significant hemorrhage. With this career development award, the PI will gain practical experience with a large-scale Phase III acute stroke clinical trial, obtain exposure to innovative reperfusion strategies, and pursue formal training in biostatistics and clinical trial methodology through introductory and advanced coursework. The PI will become an expert on acute stroke reperfusion therapies, and particularly hemorrhagic transformation, with the skills to implement an acute stroke clinical trial independently. Relevance to Public Health: Despite the availability of an effective treatment for strokes due to blocked arteries (88% of all strokes) since 1996, stroke remains the third leading cause of death and the leading cause of disability in the United States. Therapies that restore blood flow to more patients, and do so more effectively and safely, are greatly needed to improve outcomes after stroke. [unreadable] [unreadable]